Abstract
Background: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients’ life span.
Methods: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients’ underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs.
Results: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6–149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31–0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13–5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0–75.6) and 78.0 years for female patients (95% CI: 76.4–79.5) compared to 72.1 and 80.1 years for the general population.
Conclusions: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers.
AGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients’ life span is comparable to that of the general population.
Key Messages
Introduction
Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) (OMIM#105120) is an autosomal dominantly inherited systemic amyloidosis. This disease is also known as hereditary gelsolin amyloidosis (HGA), familial amyloidosis of Finnish type (FAF) and Meretoja’s disease, according to the ophthalmologist Jouko Meretoja, who first described the disease in 1969 (Citation1). The exact number of patients is unknown, but estimations vary between 400 patients to 1000 gene carriers in Finland (Citation2,Citation3). The cause of the disease is a mutation in the gene coding for gelsolin (GSN), located on chromosome nine at q33.2 (Citation4), where guanine is replaced by adenosine (640G > A), previously known as c.G654G > A (Citation4,Citation5). The same mutation has also been reported from several other European countries, as well as North America, Asia and Mexico (Citation3,Citation6,Citation7), while in Denmark, former Czechoslovakia, France and Brazil, GSN c.640G > T causes the disease (Citation3).
The symptoms of AGel amyloidosis are thought to be a consequence of GSN amyloid (AGel) fibrils and pre-amyloid oligomers, which originate from the variant misfolded GSN molecule and accumulate in various tissues (Citation3). The characteristic clinical manifestations of AGel amyloidosis include slowly progressive ophthalmologic (corneal lattice dystrophy), neurological (cranial, bifacial neuropathy in particular) and dermatological (cutis laxa) signs, which often manifest in patients in their 30s and 40s (Citation3,Citation8). The penetrance of the GSN c.640G > A mutation is 100%, but for yet unknown reasons, the disease manifestations and their severity vary significantly between patients (Citation3). The pathogenesis of AGel amyloidosis is already fairly well known (Citation9), and researchers have already taken the first steps towards developing a targeted therapy for the disease (Citation10,Citation11).
AGel amyloidosis has been assumed to have a minor effect on the expected life span (Citation12), but systematic studies on its late phases have not been available. However, some of its manifestations may even be fatal. These manifestations include generalised amyloid angiopathy (Citation13), which involves the arteries of almost every organ and may cause vascular wall fragility. Renal amyloidosis in homozygous GSN c.640G > A carriers can lead to nephrotic syndrome in patients already in their early 20s (Citation14,Citation15) and may even represent an underestimated complication in heterozygotes (Citation8). Various cardiac manifestations, such as conduction defects (Citation16) and valvulopathies (Citation17,Citation18), could also have a lethal outcome. Further, progressive cranial neuropathy, leading to bulbar palsy and oropharyngeal tissue laxity, may increase the risk of aspiration pneumonia (Citation3). Lastly, patients with AGel amyloidosis show symptoms of depression more frequently than does the general population (Citation19).
As a hereditary disease, the impact of AGel amyloidosis on life span puzzles not only the patients themselves, but also their offspring and surrounding society. As far as we know, no previous systematic studies have explored the causes of death (CoD) in patients with AGel amyloidosis. Therefore, we conducted a study of the underlying and immediate CoDs based on the death certificates of 272 deceased Finnish patients and compared the findings to data derived from death certificates of the general Finnish population.
Materials and methods
The study was based on 272 death certificates of deceased AGel amyloidosis patients. The underlying CoD was analysable in 267 patients (126 men and 141 women; mean age at death 74.4 years, range 33.9–96.2 years; death year 1969–2014), as was the immediate CoD in 203 patients (95 men and 108 women; mean age at death 75.8 years, range 44.4–94.8 years; death year 1987–2014). AGel amyloidosis typically manifests only in adulthood (Citation3), and thus, all identified patients were over the age of 30 at death.
To identify the study patients, we interviewed a total of 184 (87%) of 211 living AGel patients included in the National Finnish gelsolin amyloidosis patient registry FIN-GAR by phone and requested information about deceased relatives with AGel amyloidosis. AGel amyloidosis typically manifests with characteristic prominent facial drooping, due to bifacial paresis and cutis laxa, which is easily recognisable as premature facial aging (Citation20), in patients independent of their ethnic origin (Citation3). Genealogical data on Finnish families with AGel amyloidosis and data from the previous AGel amyloidosis studies since the 1980s (Citation3) served to complement and verify the data provided to us. Thereafter, we searched the Finnish Population Register Centre for the patients’ identity numbers and collected their death certificates from Statistics Finland. From each death certificate (n = 272), we recorded the patient’s age at death as well as the underlying and immediate CoD.
For comparison, we used statistical data on CoDs in the general Finnish population. Comparison data for the underlying CoD were available beginning in 1969, and for the immediate CoD, in 1987. The sample included only patients who had died during these years or later. Because all of the patients were over the age of 30 at death, the comparison data included only data on people who died at the age of 30 or older.
In the comparison of data, the underlying CoDs had been readily classified into 54 disease categories (Citation21); for this reason, we used an equivalent classification for the patient data. For the immediate CoD, the comparison data consisted of the Finnish Classification of Diseases 1987 (largely equivalent to the ICD-9 classification) and of the ICD-10 diagnosis codes to three-digit accuracy. We manually organised the comparison data into the 54 corresponding categories. As in the comparison data, the diagnosis codes were available only to three-digit accuracy, and some of the 54 disease categories would require four-digit accuracy; thus, the comparison data for the immediate CoD may contain slight inaccuracies. We did not analyse the most influenced disease categories 39–41 (Other diseases, symptoms and signs, not elsewhere classified; Ill-defined and unknown causes of death; Alcohol-related diseases and accidental alcohol poisoning), 48 (Accidental poisonings) and 53 (Other external causes and sequelae) for immediate CoD; these categories included a total of eight patients.
We analysed both underlying and immediate CoDs for the patient group as a whole, as well as for patient groups based on sex and age (30–59, 60–69, 70–79 and 80–99 years). We analysed the underlying and immediate CoDs independently from each other. The baseline information on the patient groups studied appears in .
Table 1. Characte ristics of AGel amyloidosis patients with death certificate available.
We compared the CoDs of the patients with the CoDs of the general population by calculating the proportional mortality ratios (PMR) for all disease categories. We calculated the PMR for a specific CoD by dividing the number of patients who died of that particular CoD by the expected number of deaths based on the general Finnish population. We then standardised the PMRs for sex and age using the age groups mentioned previously (Citation22). Assuming that the number of deaths followed a Poisson distribution, we used the chi-square distribution to calculate the exact 95% confidence intervals (CI) for the PMRs. The PMR allows for the straightforward determination of whether a particular cause of death is more likely for the patient group than for the general population (in which case PMR > 1) or less likely (in which case PMR < 1). If the confidence interval is above 1 for a particular disease, the number of deaths for patients significantly exceeds the number of expected deaths based on the general population (and if the confidence interval is below 1, it is significantly smaller) at the p < 0.05 level (Citation22).
We investigated patients’ life span separately. Because comparison data were available only from 1980 onwards, the sample included only patients who died in 1980–2014. Therefore, we investigated age at death for 231 patients (103 males and 128 females). Because age at death was skewed, we logarithmically transformed the data to calculate the geometric mean age at death and the associated 95% confidence interval. We then compared the results to statistical data on age at death among the general Finnish population (Citation23), including persons who had died at the age of 30 or older.
The local Ethics Committee of the Helsinki University Hospital approved the study.
Results
PMRs for underlying and immediate CoDs for selected medical conditions in the entire patient group, as well as for male and female patients separately, appear in and , respectively. The following presents primarily results showing a statistically significant difference between the patients and the general population.
Table 2. Proportional mortality ratios (PMR) for selected medical conditions for AGel amyloidosis patients, underlying causes of death.
Table 3. Proportional mortality ratios (PMR) for selected medical conditions for AGel amyloidosis patients, immediate causes of death.
AGel amyloidosis
AGel amyloidosis was considered the underlying CoD in 53 (19.9%) AGel amyloidosis patients (PMR = 114.2; 95% CI: 85.6–149.4). The difference between these patients and the general population was similar in both male (PMR = 156.8; 95% CI: 102.5–229.8) and female (PMR = 91.3; 95% CI: 60.2–132.8) patients. The difference was statistically significant in all the age groups studied (30–59 years PMR = 39.3, 95% CI: 8.11–114.9; 60–69 years PMR = 44.6, 95% CI: 14.5–104.0; 70–79 years PMR = 123.3, 95% CI: 76.3–188.5; 80–99 years PMR = 233.6, 95% CI: 149.7–347.6). The control group included various other diagnoses belonging to the disease category “Other endocrine, nutritional and metabolic diseases”, whereas the study patients were diagnosed only with AGel amyloidosis as their underlying CoD (no other diagnoses from this category). In the three oldest age groups, the portion of patients diagnosed with AGel amyloidosis as their underlying CoD correlated with their age at death, rising as high as 27.0% in the group aged 80–99 years. The most common immediate CoD of the patients diagnosed with AGel amyloidosis as their underlying CoD were AGel amyloidosis (n = 18) and pneumonia (n = 17).
Cancer
Cancer as an underlying CoD was significantly less common (9.7%) in the entire patient group than in the general population (PMR = 0.47; 95% CI: 0.31–0.69) or in either men (PMR = 0.46; 95% CI: 0.25–0.79) or women (PMR = 0.44; 95% CI: 0.23–0.75) separately. We also noted analogous statistically significant differences in age groups 70–79 years (PMR = 0.29; 95% CI: 0.12–0.60) and 80–99 years (PMR = 0.41; 95% CI: 0.13–0.97) separately. We also studied possible differences in fatal cancer types. Cancers of the larynx, trachea, bronchus and lungs caused death statistically significantly less often in the patient group (PMR = 0.18; 95% CI: 0.02–0.64). Patients also had fewer cases of fatal breast cancers (PMR = 0.22; 95% CI: 0.01–1.23), but the difference did not reach statistical significance. Of all the cancer types studied, only melanoma occurred more often as a CoD in AGel amyloidosis patients than in the general population (PMR = 1.31; 95% CI: 0.03–7.31), but again, this difference did not reach statistical significance.
Genitourinary diseases
Diseases of the genitourinary system were overrepresented in the female patients as the immediate CoD (PMR = 2.82; 95% CI: 1.13–5.81). Moreover, the entire patient group was 2.29 times more likely to die of a renal complication (95% CI: 0.99–4.52), but this difference did not quite reach statistical significance. All but one of these patients (n = 8) died of a renal disease (one died of an unclear haemorrhage). Their immediate CoDs were glomerular disease related to amyloidosis, acute tubule-interstitial nephritis and nephrotic syndrome (two cases of each), and acute renal failure (one case).
Life span
The mean life span for male patients in the group studied was 73.9 years (95% CI: 72.0–75.6), whereas in the general population, the age at death for men who died at the age of 30 or older was 72.1 years. Male patients lived on average 1.8 years longer than men in general, but the difference falls within the confidence interval. The female patients died at a mean age of 78.0 years (95% CI: 76.4–79.5), whereas the mean age at death in the general population was 80.1 years. Female patients lived on average a 1.9-year shorter life, which is a statistically significant difference.
Discussion
In this study, we investigated the CoD of AGel amyloidosis patients. We collected a total of 272 death certificates, which, to our knowledge, is the largest systematic collection of material on this subject thus far. Previously, studies have reported only sporadic observations of possible CoDs (Citation24,Citation13,Citation15,Citation25). This study shows that the death of a significant percentage (20%) of the patients was attributed to AGel amyloidosis. The exact fatal mechanisms of AGel amyloidosis require more thorough investigation.
The most important finding of this study was that AGel amyloidosis patients died significantly less frequently of cancer than did the general population. The frequency of fatal respiratory tract cancers was especially low, followed by that of breast cancer, while of all the different malignant neoplasms, only fatal melanoma was slightly more common in our patients than in the general population. Thus far, no data on a possible association between malignant disorders and AGel amyloidosis has been presented.
In AGel amyloidosis, the GSN metabolism is altered intracellularly, and the disease results in, for example, elevated GSN serum levels (Citation26). At present, whether such altered GSN metabolism could offer some protective effect, even though GSN is known to promote health in various ways, remains unknown (Citation27). GSN is a principal actin-modulating protein that plays a role in cell motility (Citation28) and in the control of cell growth, morphology and apoptosis (Citation29). GSN is widely distributed in human tissues and occurs in intracellular (cytoplasmic) and secreted (plasma) forms, and as GSN-3 in cerebral oligodendrocytes, the lungs and testes (Citation30). GSN also plays various roles in cancer development and it also has tumour-suppressive potential (Citation31). GSN expression is downregulated in various cancers, such as gastric, bladder, colon, lung (Citation31) and breast (Citation32). Gelsolin overexpression may inhibit tumour growth (Citation33), but also promotes tumour cell motility, invasion (Citation34), (Citation35) and metastatic capacity (Citation36). Interestingly, GSN may be of special importance in the development of lung cancer (Citation37,Citation38). The marked reduction in fatal lung cancers noted here, however, may relate to the fact that lung cancer has the highest cancer mortality in Finland (Citation39). In any event, how the GSN c.640G > A mutation and its consequences might relate to the progression of lung and other cancers in AGel amyloidosis patients currently remains unknown.
Diseases of the genitourinary tract (in 7 of 8 cases, a renal disease) were prominent as immediate CoDs, especially in female patients. This study provides strong evidence that renal manifestations, as Meretoja (Citation12) already suggested, may prove lethal, even though in heterozygotes, renal consequences are usually mild (Citation2). Unexpectedly, frequent renal transplantations were recently reported among heterozygous patients (Citation8), which supports the finding of this study.
Interestingly, although a fifth of patients with AGel amyloidosis were considered to have died of the disease, its influence on the patients’ life span was rather small, which is well in line with previous findings (Citation12). One explanation might relate to the wide variability of the clinical manifestations of the disease; presumably, there is a proportion of patients in whom the sequelae of the disease on the tissue level are more serious than in other patients, thereby leading to their death. Further, this study suggests that the rarity of cancer deaths may represent a positive impact on the patients’ life span.
This study has some limitations. Firstly, the sample might have included patients who did not carry the GSN c.640G > A mutation. The estimated risk of this is small, because AGel amyloidosis substantially influences the facial appearance, and patients generally have in-depth knowledge of their ancestors and other family members with AGel amyloidosis. Further, the number of affected families in Finland is limited. Secondly, instead of investigating the deceased patients by ourselves, the study was based on the death certificates, usually completed by the treating physician. The comparison data, however, are based on information collected in a similar way (death certificates of the general population) and are therefore subject to similar flaws. Finally, because AGel amyloidosis is a rare disease and data on these patients are incomplete, our sample size was limited.
This first systematic study of the late phases of AGel amyloidosis shows that the cause of death for a significant number of the patients was attributed to AGel amyloidosis. The results will be refined along with the development of clinical register systems to more effectively identify and follow patients with AGel amyloidosis and such efforts have already begun in Finland with FIN-GAR (Citation8). The significantly smaller frequency of deaths due to malignancies in AGel amyloidosis patients, compared to deaths in the general Finnish population, which may contribute to the relatively long life span of patients despite complications from AGel amyloidosis, is a keenly interesting finding that deserves more thorough investigation.
Funding information
We are grateful to the Kymenlaakso Regional Fund of the Finnish Cultural Foundation [35151358], the Helsinki University Hospital Research Fund [TYH2014111] and to Finska Läkaresällskapet for their financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgements
We thank our Finnish AGel amyloidosis patients and their patient organisation SAMY for their considerable support during this study.
Disclosure statement
The authors report no conflicts of interest.
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